New Compounds

ABSTRACT

The novel optically pure compounds Na + , Mg 2+ , Li + , K + , Ca 2+  and N + (R) 4  salts of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole or (−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, in particular sodium and magnesium salt form thereof, where R is an alkyl with 1-4 carbon atoms, processes for the preparation thereof and pharmaceutical preparations containing the compounds as active ingredients, as well as the use of the compounds in pharmaceutical preparations and intermediates obtained by preparing the compounds.

This application is a continuation-in-part of copending Ser. No.08/256,174.

FIELD OF THE INVENTION

The present invention is directed to new compounds of high opticalpurity and crystalline salts thereof, their use in medicine, a processfor their preparation and their use in the manufacture of pharmaceuticalpreparation. The invention also relates to novel intermediates in thepreparation of the compounds of the invention.

BACKGROUND OF THE INVENTION

The compound5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,having the generic name omeprazole, and therapeutically acceptablealkaline salts thereof are described in U.S. Pat. No. 4,255,431 toJunggren et al., EP 5129 and EP 124 495, respectively. Omeprazole andits alkaline salts are effective gastric acid secretion inhibitors, andare useful as antiulcer agents. The compounds, being sulfoxides, have anasymmetric center in the sulfur atom, i.e. exist as two optical isomers(enantiomers).

The separation of the enantiomers of omeprazole in analytical scale isdescribed in e.g. J. Chromatography, 532 (1990), 305-19 and in apreparative scale in DE 4035455. The latter has been done by using adiastereomeric ether which is separated and thereafter hydrolysed in anacidic solution. Under the acidic conditions needed for hydrolysis ofthe attached group, omeprazole is quite sensitive and the acid has to bequickly neutralized with a base to avoid degradation of theacid-sensitive compound. In the above mentioned application (DE 4035455)this is done by adding the reaction mixture containing concentratedsulfuric acid to a concentrated solution of NaOH. This isdisadvantageous because there is a great risk of locally reaching pHvalues between 1-6, which would be devastating for the substance.Moreover, instantaneous neutralization will create heat which will bedifficult to handle in large scale production.

There is no example in the known prior art of any isolated orcharacterized salt of optically pure omeprazole, i.e. of singleenantiomers of omeprazole or of any isolated or characterized salt ofany optically pure omeprazole analogue.

SUMMARY OF THE INVENTION

It is desirable to obtain compounds with improved pharmacokinetic andmetabolic properties which will give an improved therapeutic profilesuch as a lower degree of interindividual variation. The presentinvention provides such compounds, which are novel salts of singleenantiomers of omeprazole.

A preferred embodiment of the present invention provides purecrystalline enantiomeric salts of omeprazole and methods for thepreparation thereof.

A more preferred embodiment of the present invention is directed to anoptically pure crystalline enantiomeric magnesium salt of omeprazole andmethod for the preparation thereof.

A nonaqueous process according to the present invention is directed tothe preparation of crystalline forms of an optically pure enantiomer ofomeprazole magnesium salt or analogues thereof which includes steps ofstirring a crude preparation of the omeprazole enantiomer under nitrogeninto a methanolic magnesium methoxide solution, precipitating inorganicmagnesium salt with addition of a small amount of water, removing anyprecipitated inorganic magnesium salts, concentrating the residualmethanolic solution, precipitating the omeprazole enantiomer by addingacetone to the residual solution, and filtering off the optically pureenantiomer crystals of magnesium omeprazole or analogues thereof.

The present invention in a further aspect provides a novel method forpreparing the novel compounds of the invention in large scale. Thisnovel method can also be used in large scale to obtain singleenantiomers of omeprazole in neutral form.

The compounds according to the invention may be used for inhibitinggastric acid secretion in mammals and man. In a more general sense, thecompounds of the invention may be used for the treatment of gastricacid-related diseases and gastrointestinal inflammatory diseases inmammals and man, such as gastric ulcer, duodenal ulcer, refluxesophagitis, and gastritis. Furthermore, the compounds may be used fortreatment of other gastrointestinal disorders where gastricantisecretory effect is desirable e.g. in patients on NSAID therapy, inpatients with gastrinomas, and in patients with acute uppergastrointestinal bleeding. They may also be used in patients inintensive care situations, and pre- and postoperatively to prevent acidaspiration and stress ulceration. The compound of the invention may alsobe used for treatment or prophylaxis of inflammatory conditions inmammals, including man, especially those involving lysozymal enzymes.Conditions that may be specifically mentioned for treatment arerheumatoid arthritis and gout. The compound of the invention may also beuseful in the treatment of psoriasis as well as in the treatment ofHelicobacter infections.

DETAILED DESCRIPTION OF THE INVENTION

The present invention refers to the new Na⁺, Mg²⁺, Li⁺, K⁺, Ca²⁺ andN⁺(R)₄ salts of the single enantiomers of omeprazole, where R is analkyl with 1-4 carbon atoms, i.e. Na⁺, Mg²⁺, Li⁺, K⁺, Ca²⁺ and N⁺(R)₄salts of(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleand(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,where R is an alkyl with 1-4 carbon atoms.

Particularly preferred salts according to the invention are the Na⁺,Ca²⁺ and Mg²⁺ salts, i.e(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt,(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt,(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt,(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt,(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolecalcium salt and(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolecalcium salt.

Most preferred salts according to the invention are the optically pureNa⁺ salts of omeprazole according to compounds Ia and Ib

and the optically pure magnesium salts of omeprazole according tocompounds IIa and IIb

With the expression “optically pure Na⁺ salts of omeprazole” is meantthe (+)-enantiomer of omeprazole Na-salt essentially free of the(−)-enantiomer of omeprazole Na-salt and the (−)-enantiomer essentiallyfree of the (+)-enantiomer, respectively. Single enantiomers ofomeprazole have hitherto only been obtained as syrups and not ascrystalline products. The salts defined by the present invention areeasy to obtain by means of the novel specific method according to oneaspect of the invention of preparing the single enantiomers ofomeprazole. In contrast to the neutral forms the salts can be obtainedas crystalline products. Because it is possible to purify opticallyimpure or partially pure salts of the enantiomers of omeprazole bycrystallization, they can be obtained in very high optical purity,namely ≧99.8% enantiomeric excess (e.e.) even from an opticallycontaminated preparation. Moreover, the optically pure salts are stableresisting racemization both in neutral pH and basic pH, which issurprising since the known deprotonation at the carbon atom between thepyridine ring and the chiral sulfur atom was expected to causeracemization under alkaline conditions. This high stability againstracemization makes it possible to use a single enantiomeric salt of theinvention in therapy.

The specific method of preparation of the single enantiomers ofomeprazole is a further aspect of the invention as mentioned above andit can be used to obtain the single enantiomers of omeprazole in neutralform as well as the salts thereof.

Yet a further aspect of the invention is the compound III, which is anintermediate used in the specific method of preparation.

Preparation

The optically pure compounds of the invention, i.e. the singleenantiomers, are prepared by separating the two stereoisomers of adiastereomeric mixture of the following type, 5- or6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[acyloxymethyl]-1H-benzimidazole,formula IV

wherein the methoxy substituent in the benzimidazole moiety is inposition 5 or 6, and wherein the Acyl radical is as defined below,followed by a solvolysis of each separated diastereomer in an alkalinesolution. The formed single enantiomers of omeprazole are then isolatedby neutralizing aqueous solutions of the salts of the single enantiomersof omeprazole with a neutralizing agent which can be an acid or an estersuch as methyl formate.

The Acyl moiety in the diastereomeric ester may be a chiral acyl groupsuch as mandeloyl, and the asymmetric center in the chiral acyl groupcan have either R or S configuration.

The diastereomeric esters can be separated either by chromatography orfractional crystallization.

The solvolysis usually takes place together with a base in a proticsolvent such as alcohols or water, but the acyl group may also behydrolyzed off by a base in an aprotic solvent such as dimethylsulfoxideor dimethylformamide. The reacting base may be OH⁻ or R¹O⁻ where R¹ canbe any alkyl or aryl group.

To obtain the optically pure Na⁺ salts of the invention, i.e. the singleenantiomers of omeprazole Na⁺ salts, the resulting compound is treatedwith a base, such as NaOH, in an aqueous or nonaqueous medium, or withNaOR² wherein R² is an alkyl group containing 1-4 carbon atoms, or withNaNH₂. In addition, alkaline salts wherein the cation is Li⁺ or K⁺ maybe prepared using lithium or potassium salts of the above mentionedbases. In order to obtain the crystalline form of the Na⁺ salt, additionof NaOH in a non-aqueous medium such as a mixture of 2-butanone andtoluene, is preferred.

To obtain the optically pure Mg²⁺ salts of the invention, optically pureenantiomeric Na⁺ salts may be treated with an aqueous solution of aninorganic magnesium salt such as MgCl₂, whereupon the Mg²⁺ salts areprecipitated. The optically pure Mg²⁺ salts may also be prepared bytreating single enantiomers of omeprazole with a base, such as Mg(OR³)₂,wherein R³ is an alkyl group containing 1-4 carbon atoms, in anon-aqueous solvent such as alcohol (only for alcoholates), e.g. ROH, orin an ether such as tetrahydrofuran. In an analogous way, also alkalinesalts wherein the cation is Ca²⁺ can be prepared, using an aqueoussolution of an inorganic calcium salt such as CaCl₂.

Alkaline salts of the single enantiomers of the invention are, asmentioned above, beside the sodium salts (compounds Ia and Ib) and themagnesium salts (compounds IIa and IIb), exemplified by their salts withLi⁺, K⁺, Ca²⁺ and N⁺(R)₄, where R is an alkyl with 1-4 C-atoms.

For clinical use the single enantiomers, i.e. the optically purecompounds, of the invention are formulated into pharmaceuticalformulations for oral, rectal, parenteral or other modes ofadministrations. The pharmaceutical formulations contain the singleenantiomers of the invention normally in combination with apharmaceutically acceptable carrier. The carrier may be in form of asolid, semi-solid or liquid diluent, or capsule. These pharmaceuticalpreparations are a further object of the invention. Usually the amountof active compound is between 0.1-95% by weight of the preparation,between 0.2-20% by weight in preparations for parenteral use and between1-50% by weight in preparations for oral administration.

In the preparation of pharmaceutical formulations in form of dosageunits for oral administration the optically pure compound may be mixedwith a solid, powdered carrier, such as lactose, saccharose, sorbitol,mannitol, starch, amylopectin, cellulose derivates, gelatin or anothersuitable carrier, stabilizing substances such as alkaline compounds e.g.carbonates, hydroxides and oxides of sodium, potassium, calcium,magnesium and the like as well as with lubricating agents such asmagnesium stearate, calcium stearate, sodium stearyl fumarate andpolyethyleneglycol waxes. The mixture is then processed into granules orpressed into tablets. Granules and tablets may be coated with an entericcoating which protects the active compound from acid catalyzeddegradation as long as the dosage form remains in the stomach. Theenteric coating is chosen among pharmaceutically acceptableenteric-coating materials e.g. beeswax, shellac or anionic film-formingpolymers and the like, if preferred in combination with a suitableplasticizer. To the coating various dyes may be added in order todistinguish among tablets or granules with different amounts of theactive compound present.

Soft gelatine capsules may be prepared with capsules containing amixture of the active compound, vegetable oil, fat, or other suitablevehicle for soft gelatine capsules. Soft gelatine capsules may also beenteric-coated as described above.

Hard gelatine capsules may contain granules or enteric-coated granulesof the active compound. Hard gelatine capsules may also contain theactive compound in combination with a solid powdered carrier such aslactose, saccharose, sorbitol, mannitol, potato starch, amylopectin,cellulose derivates or gelatin. The capsules may be enteric-coated asdescribed above.

Dosage units for rectal administration may be prepared in the form ofsuppositories which contain the active substance mixed with a neutralfat base, or they may be prepared in the form of a gelatine rectalcapsule which contains the active substance in a mixture with avegetable oil, paraffin oil or other suitable vehicle for gelatinerectal capsules, or they may be prepared in the form of a ready-mademicro enema, or they may be prepared in the form of a dry micro enemaformulation to be reconstituted in a suitable solvent just prior toadministration.

Liquid preparation for oral administration may be prepared in the formof syrups or suspensions, e.g. solutions or suspensions containing from0.2% to 20% by weight of the active ingredient and the remainderconsisting of sugar or sugar alcohols and a mixture of ethanol, water,glycerol, propylene glycol and/or polyethylene glycol. If desired, suchliquid preparations may contain coloring agents, flavoring agents,saccharine and carboxymethyl cellulose or other thickening agents.Liquid preparations for oral administration may also be prepared in theform of dry powder to be reconstituted with a suitable solvent prior touse.

Solutions for parenteral administrations may be prepared as solutions ofthe optically pure compounds of the invention in pharmaceuticallyacceptable solvents, preferably in a concentration from 0.1 to 10% byweight. These solutions may also contain stabilizing agents and/orbuffering agents and may be manufactured in different unit dose ampoulesor vials. Solutions for parenteral administration may also be preparedas dry preparations to be reconstituted with a suitable solventextemporaneously before use.

The typical daily dose of the active compound will depend on variousfactors such as for example the individual requirement of each patient,the route of administration and the disease. In general, oral andparenteral dosages will be in the range of 5 to 500 mg per day of activesubstance.

The invention is illustrated by the following examples using preferredprocedures for the preparation of optically pure sodium salts andmagnesium salts.

The processes described below for optically pure enantiomeric sodiumsalts of omeprazole result in change of directions from (−) to (+)optical rotation and, vice versa, from (+) to (−) optical rotation whenpreparing the sodium salt from the neutral form of omeprazole and again,when preparing the magnesium salt from the sodium salt of omeprazole.

Example 1 Preparation of(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt

100 mg (0.3 mmol) of(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(contaminated with 3% of the (+)-isomer) was dissolved in 1 ml of2-butanone with stirring. 60 μl of an aqueous solution of 5.0M sodiumhydroxide and 2 ml of toluene were added. The resultant mixture wasnon-homogeneous. In order to obtain a clear solution, more 2-butanonewas added (ca 1 ml) and the mixture was stirred at ambient temperatureover night. The formed precipitate was filtered off and washed withether. There was obtained 51 mg (46%) of the title compound as whitecrystals m.p. (decomposition) 246-248° C. The optical purity (e.e.)which was analyzed by chiral column chromatography was ≧99.8%. [α]_(D)²⁰=+42.8° (concentration, c=0.5%, water).

NMR data are given below.

Example 2 Preparation of(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt

100 mg-(0.3 mmol) of(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole(contaminated with 3% of the (−)-isomer) was dissolved in 1 ml of2-butanone with stirring. 60 μl of an aqueous solution of 5.0 M sodiumhydroxide and 2 ml of toluene were added. The resultant mixture wasnon-homogeneous. In order to obtain a clear solution, more 2-butanonewas added (ca 1 ml) and the mixture was stirred at ambient temperatureover night. The formed precipitate was filtered off and washed withether. There was obtained 56 mg (51%) of the title compound as whitecrystals m.p. (decomposition) 247-249° C. The optical purity (e.e.)which was analyzed by chiral column chromatography was ≧99.8%. [α]_(D)²⁰=−44.1° (c=0.5%, water).

NMR data are given below.

Example 3 Preparation of(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt

2.9 ml of a 0.1 M solution of NaOH was added to 0.10 g (0.29 mmol)(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.To this mixture 2 ml methylene chloride was added, and after mixing in aseparatory funnel the aqueous solution was separated off. A solution of14 mg (0.145 mmol) MgCl₂ in water was added dropwise. The formedprecipitate was isolated by centrifugation, and 52 mg (50%) of theproduct was isolated as an amorphous powder. The optical purity (e.e.)was 98%, and thus the same as the starting material. The optical puritywas determined by chromatography on an analytical chiral column. [α]_(D)²⁰=+101.2° (c=1%, methanol). The Mg content of the sample was found tobe 3.0%, shown by atomic absorption spectroscopy.

Example 4 Preparation of(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt

(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt (0.500 g, 1.36 mmol) was dissolved in water (10 ml). To thismixture 10 ml of an aqueous solution of MgCl₂xH₂O (138 mg, 0.68 mmol)was added dropwise and the formed precipitate was isolated bycentrifugation. There was obtained 418 mg (86%) of the product as awhite powder. The optical purity (ee) of the product was 99.8% which wasthe same as the optical purity of the starting material. The opticalpurity was determined by chromatography on an analytical chiral column.[α]_(D) ²⁰=+129.9° (c=1%, methanol).

Example 5 Preparation of(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolemagnesium salt

(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazolesodium salt (0.165 g, 0.45 mmol) was dissolved in water (3 ml). To thismixture 2 ml of an aqueous solution of MgCl₂xH₂O (46 mg, 0.23 mmol) wasadded dropwise and the formed precipitate was isolated bycentrifugation. There was obtained 85 mg (51%) of the product as a whitepowder. The optical purity (ee) of the product was 99.9% which was thesame or better as the optical purity of the starting material. Theoptical purity was determined by chromatography on an analytical chiralcolumn. [α]_(D) ²⁰=−128.2° (c=1%, methanol).

TABLE 1 Ex. Solvent NMR data δ ppm 1. DMSO-d₆ 2.20 (s, 3H), 2.22 (s,3H), 3.69 (s, 3H), 3.72 (s, 3H), 500 MHz 4.37 (d, 1H), 4.75 (d, 1H),6.54 (dd, 1H), 6.96 (d, 1H) 7.30 (d, 1H), 8.21 (s, 1H). 2. DMSO-d₆ 2.20(s, 3H), 2.22 (s, 3H), 3.69 (s, 3H), 3.72 (s, 3H), 500 MHz 4.38 (d, 1H),4.73 (d, 1H), 6.54 (dd, 1H), 6.96 (d, 1H), 7.31 (d, 1H), 8.21 (s, 1H).

A preferred method for preparing optically pure omeprazole enantiomercrystal salts of magnesium is described in Examples 6 and 7.

Example 6 Enhancement of the Optical Purity by Preparing the MagnesiumSalt of(−)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolein Nonaqueous Solution Followed by Crystallization of Said Salt

Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted with methanol (50ml) at 40° C. with a catalytic amount of methylene chloride. Thereaction was run under nitrogen and was finished after five hours. Atroom temperature a mixture of the two enantiomers [90% (−)-isomer and10% (+)-isomer] of5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. Themixture was stirred for 12 hours whereupon a small amount of water (0.1ml) was added in order to precipitate inorganic magnesium salts. After30 minutes stirring, these inorganic salts were filtered off and thesolution was concentrated on a rotavapor. The residue was now aconcentrated methanolic solution of the enantiomeric mixture (i.e. thetitle compound contaminated with the (+)-isomer), with an optical purity(enantiomeric excess, e.e.) of 80%. This mixture was diluted withacetone (100 ml) and after stirring at room temperature for 15 minutes,a white precipitate was obtained. Additional stirring for 15 minutes andthereafter filtration afforded 1.3 g (50%) of the title compound aswhite crystals. Chiral analyses of the crystals and mother liquor wereperformed by chromatography on an analytical chiral column. The opticalpurity of the crystals and mother liquor was found to be 98.4 e.e. and64.4% e.e., respectively. Thus, the optical purity (e.e.) has beenenhanced from 80% to 98.4% simply by crystallizing the Mg-salt from amixture of acetone and methanol. The product was crystalline as shown bypowder X-ray diffraction and the magnesium content was 3.44% as shown byatomic absorption spectroscopy. [α]_(D) ²⁰=−131.5° (c=0.5%, methanol).

Example 7 Enhancement of the Optical Purity by Preparing the MagnesiumSalt of(+)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolein Nonaqueous Solution Followed by Crystallization of Said Salt

Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted with methanol (50ml) at 40° C. with a catalytic amount of methylene chloride. Thereaction was run under nitrogen and was finished after five hours. Atroom temperature a mixture of the two enantiomers [90% (+)-isomer and10% (−)-isomer] of5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. Themixture was stirred for 12 hours whereupon a small amount of water (0.1ml) was added in order to precipitate inorganic magnesium salts. After30 minutes stirring, these inorganic salts were filtered off and thesolution was concentrated on a rotavapor. The residue was now aconcentrated methanolic solution of the enantiomeric mixture (i.e. thetitle compound contaminated with the (−)-isomer), with an optical purity(e.e.) of 80%. This mixture was diluted with acetone (100 ml) and afterstirring at room temperature for one hour, a white precipitate wasobtained. Additional stirring for 30 minutes and thereafter filtrationafforded 0.35 g of the title compound as white crystals. Additionalstirring of the mother liquor for 24 hours at room temperature affordedanother 1.0 g (total yield=52%). Chiral analyses of the crystals and thesecond mother liquor were performed by chromatography on an analyticalchiral column. The optical purity of the two crystal fractions was 98.8%e.e. and 99.5% e.e. respectively. The optical purity of the motherliquor was found to be 57% e.e. Thus, the optical purity (e.e.) has beenenhanced from 80% to approximately 99% simply by crystallizing theMg-salt from a mixture of acetone and methanol. The first precipitationwas crystalline as shown by powder X-ray diffraction and the magnesiumcontent of the same fraction was 3.49% as shown by atomic absorptionspectroscopy. [α]_(D) ²⁰=+135.6° (c=0.5%, methanol).

The crystalline salt according to Example 6 is most preferred.

Preparation of the Synthetic Intermediates According to the Invention isDescribed in the following examples.

Example 8 Preparation of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-(R/S)-sulfinyl]-1-[(R)-mandeloyloxymethyl]-1H-benzimidazole

A solution of 3.4 g sodium hydroxide in 40 ml water was added to amixture of 14.4 g (42 mmol) tetrabutylammonium hydrogen sulfate and 6.4g (42 mmol) (R)-(−)-mandelic acid. The mixture was extracted with 400 mlchloroform. After separation, the organic extract was heated to refluxwith 16.6 g (42 mmol) of the racemate of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1-[chloromethyl]-1H-benzimidazole.Evaporation of the solvent was followed by dilution with 100 mldichloromethane and 700 ml ethyl acetate. The mixture was washed with3×200 ml water and the organic solution was dried over MgSO₄ and thenevaporated. The crude material was purified by recrystallization from100 ml acetonitrile, giving 8.1 g of the title compound (38%) as adiastereomeric mixture.

NMR data are given below.

Example 9 Separation of the More Hydrophilic Diastereomer of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-(R/S)-sulfinyl]-1[(R)mandeloyloxymethyl]-1H-benzimidazole

The diastereomers of the title compound in Example 8 were separatedusing reversed phase chromatography (HPLC). Approximately 300 mg of thediastereomeric mixture was dissolved in 10 ml hot acetonitrile which wasdiluted with 10 ml of a mixture of aqueous 0.1 M ammoniumacetate andacetonitrile (70/30). The solution was injected to the column and thecompounds were eluted with a mixture of aqueous 0.1 M ammoniumacetateand acetonitrile (70/30). The more hydrophilic isomer was easier toobtain pure than the less hydrophilic one. The work up procedure for thefraction which contained pure isomer was as follows; extraction withdichloromethane, washing the organic solution with aqueous 5% sodiumhydrogen carbonate solution, drying over Na₂SO₄ and evaporation of thesolvent on a rotavapor (at the end of the evaporation the removal ofacetonitrile was facilitated by adding more dichloromethane). Using 1.2g of the diastereomeric mixture with the above mentioned technique, themore hydrophilic isomer, 410 mg, was obtained in a pure state as acolorless syrup.

NMR data are given below.

Example 10 Preparation of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-(R/S)-sulfinyl]-1-[(S)-mandeloyloxymethyl]-1H-benzimidazole

The product was obtained from 8.1 g (202 mmol) sodium hydroxide in 100ml water, 34.4 g (101 mmol) tetrabutylammonium hydrogen sulfate, 15.4 g(101 mmol) (S)-(+)-mandelic acid and 39.9 g (101 mmol) of the racemateof6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1-[chloromethyl]-1H-benzimidazoleusing the same procedure as in Example 8. Recrystallization from 100 mlacetonitrile yielded 21.3 g, i.e. 41% of the title compound as adiastereomeric mixture.

NMR data are given below.

Example 11 Separation of the More Hydrophilic Diastereomer of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-(R/S)-sulfinyl]-1-[(S)-mandeloyloxymethyl]-1H-benzimidazole

The diastereomers of the title compound in Example 10 were separatedusing reversed phase chromatography (HPLC) in the same way as in Example7, but using the diasteromeric mixture of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-(R/S)-sulfinyl]-1-[(S)-mandeloloxymethyl]-1H-benzimidazoleinstead of the (R)-mandelic ester used in Example 9. Using 2.1 g of thediastereomeric mixture, the more hydrophilic isomer, 760 mg, wasobtained in a pure state as a colorless syrup.

NMR data are given below.

Example 12 Preparation of(−)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole

0.23 g (0.45 mmol) of the more hydrophilic diastereomer of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[(R)-mandeloyloxymethyl]-1H-benzimidazolewas dissolved in 15 ml methanol. A solution of 36 mg (0.9 mmol) sodiumhydroxide in 0.45 ml water was added, and after 10 minutes the mixturewas evaporated on a rotavapor. The residue was partitioned between 15 mlwater and 15 ml dichloromethane. The organic solution was extracted with15 ml water and to the combined aqueous solutions was added 85 μl (1.4mmol) methyl formate. After 15 minutes the mixture was extracted with3×10 ml dichloromethane. The organic solution was dried over Na₂SO₄ andthen evaporated. There was obtained 0.12 g (77%) of the title compoundas a colorless syrup. The optical purity (e.e.) which was analyzed bychiral column chromatography was 94%. [α]_(D) ²⁰=−155° (c=0.5%,chloroform).

NMR data are given below

Example 13 Preparation of(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole

0.76 g (1.5 mmol) of the more hydrophilic diastereomer of6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1-[(S)-mandeloyloxymethyl]-1H-benzimidazolewas dissolved in 50 ml methanol. A solution of 0.12 mg (3.0 mmol) sodiumhydroxide in 1.5 ml water was added, and after 10 minutes the mixturewas evaporated on a rotavapor. The residue was partitioned between 25 mlwater and 25 ml dichloromethane. The organic solution was extracted with25 ml water and to the combined aqueous solutions was added 200 μl (3.2mmol) methyl formate. After 15 minutes the mixture was extracted with3×25 ml dichloromethane. The organic solution was dried over Na₂SO₄ andthen evaporated. There was obtained 0.42 g (81%) of the title compoundas a colorless syrup. The optical purity (e.e.) which was analyzed bychiral column chromatography was 98%. [α]_(D) ²⁰=+157° (c=0.5%,chloroform).

NMR data are given below

TABLE 2 Ex. Solvent NMR data δ ppm 8. CDCl₃ 2.18 (s, 3H), 2.20 (s, 3H),2.36 (s, 3H), 2.39 (s, 3H), 500 MHz 3.77 (s, 3H), 3.78 (s, 3H), 3.82 (s,3H), 3.87 (s, 3H), 4.80 (d, 1H), 4.88 (d, 1H), 5.0 (m, 2H), 5.34 (s,2H), 6.43 (d, 1H), 6.54 (d, 1H), 6.6-6.7 (m, 2H), 6.90 (d, 1H),6.95-6.98 (m, 2H), 7.01 (d, 1H), 7.2-7.3 (m, 6H), 7.37 (m, 2H), 7.44 (m,2H), 7.58 (d, 1H), 7.62 (d, 1H), 7.95 (s, 1H), 7.97 (s, 1H). 9. CDCl₃2.20 (s, 3H), 2.36 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 500 MHz 4.80 (d,1H), 5.00 (d, 1H), 5.35 (d, 1H), 6.43 (d, 1H), 6.63 (d, 1H), 6.90 (d,1H), 6.97 (dd, 1H), 7.2-7.3 (m, 3H), 7.37 (m, 2H), 7.62 (d, 1H), 7.97(s, 1H). 10. CDCl₃ 2.19 (s, 3H), 2.20 (s, 3H), 2.36 (s, 3H), 2.39 (s,3H), 500 MHz 3.77 (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H),4.80 (d, 1H), 4.88 (d, 1H), 5.0 (m, 2H), 5.34 (s, 2H), 6.43 (d, 1H),6.54 (d, 1H), 6.6-6.7 (m, 2H), 6.90 (d, 1H), 6.96-6.98 (m, 2H), 7.01 (d,1H), 7.2-7.3 (m, 6H), 7.37 (m, 2H), 7.44 (m, 2H), 7.58 (d, 1H), 7.62 (d,1H), 7.95 (s, 1H), 7.97 (s, 1H). 11. CDCl₃ 2.20 (s, 3H), 2.36 (s, 3H),3.78 (s, 3H), 3.82 (s, 3H), 500 MHz 4.80 (d, 1H), 5.00 (d, 1H), 5.35 (d,1H), 6.43 (d, 1H), 6.63 (d, 1H), 6.90 (d, 1H), 6.97 (dd, 1H), 7.2-7.3(m, 3H), 7.37 (m, 2H), 7.62 (d, 1H), 7.97 (s, 1H). 12. CDCl₃ 2.18, (s,3H), 2.22 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H), 300 MHz 4.77 (m, 2H),6.93 (dd, 1H), ≈7.0 (b, 1H), ≈7.5 (b, 1H), 8.19 (s, 1H). 13. CDCl₃ 2.21(s, 3H), 2.23 (s, 3H), 3.69 (s, 3H), 3.84 (s, 3H), 4.76 (m, 2H), 6.94(dd, 1H), ≈7.0 (b, 1H), ≈7.5 (b, 1H), 8.20 (s, 1H).

Pharmaceutical preparations containing the compounds of the invention asactive ingredient are illustrated in the following formulations.

Syrup

A syrup containing 1% (weight per volume) of active substance wasprepared from the following ingredients:

Compound according to Example 1 1.0 g Sugar, powder 30.0 g Saccharine0.6 g Glycerol 5.0 g Flavoring agent 0.05 g Ethanol 96% 5.0 g Distilledwater q.s. to a final volume of 100 ml

Sugar and saccharine were dissolved in 60 g of warm water. After coolingthe active compound was added to the sugar-solution and glycerol and asolution of flavoring agents dissolved in ethanol were added. Themixture was diluted with water to a final volume of 100 ml.

Enteric-Coated Tablets

An enteric coated tablet containing 50 mg of active compound wasprepared from the following ingredients:

I Compound according to Example 6 500 g as Mg salt Lactose 700 g Methylcellulose  6 g Polyvinylpyrrolidone cross-linked  50 g Magnesiumstearate  15 g Sodium carbonate  6 g Distilled water q.s. II Celluloseacetate phthalate 200 g Cetyl alcohol  15 g Isopropanol 2000 g Methylene chloride 2000 g I Compound according to Example 6, powder, was mixed with lactose andgranulated with a water solution of methyl cellulose and sodiumcarbonate. The wet mass was forced through a sieve and the granulatedried in an oven. After drying the granulate was mixed withpolyvinylpyrrolidone and magnesium stearate. The dry mixture was pressedinto tablet cores (10 000 tablets), each tablet containing 50 mg ofactive substance, in a tabletting machine using 7 mm diameter punches.II A solution of cellulose acetate phthalate and cetyl alcohol inisopropanol/methylene chloride was sprayed onto the tablets I in anAccela Cota®, Manesty coating equipment. A final tablet weight of 110 mgwas obtained.

Solution for Intravenous Administration

A parenteral formulation for intravenous use, containing 4 mg of activecompound per ml, was prepared from the following ingredients:

Compound according to Example 2   4 g Sterile water to a final volume of1000 ml

The active compound was dissolved in water to a final volume of 1000 ml.The solution was filtered through a 0.22 μm filter and immediatelydispensed into 10 ml sterile ampoules. The ampoules were sealed.

Capsules

Capsules containing 30 mg of active compound were prepared from thefollowing ingredients:

Compound according to Example 6 300 g Lactose 700 g Microcrystallinecellulose  40 g Hydroxypropyl cellulose low-substituted  62 g Disodiumhydrogen phosphate  2 g Purified water q.s.

The active compound was mixed with the dry ingredients and granulatedwith a solution of disodium hydrogen phosphate. The wet mass was forcedthrough an extruder and spheronized and dried in a fluidized bed dryer.

500 g of the pellets above were first coated with a solution ofhydroxypropyl methylcellulose, 30 g, in water, 750 g, using a fluidizedbed coater. After drying, the pellets were coated with a second coatingas given below:

Coating Solution:

Hydroxypropyl methylcellulose phthalate  70 g Cetyl alcohol  4 g Acetone200 g Ethanol 600 g

The final coated pellets were filled into capsules.

Suppositories

Suppositories were prepared from the following ingredients using awelding procedure. Each suppository contained 40 mg of active compound.

Compound according to Example 1  4 g Witepsol H-15 180 g

The active compound was homogenously mixed with Witepsol H-15 at atemperature of 41° C. The molten mass was volume filled intopre-fabricated suppository packages to a net weight of 1.84 g. Aftercooling the packages were heat sealed. Each suppository contained 40 mgof active compound.

Stability Towards Racemization at Different pH Values

The stability of the optically pure compounds of the invention againstracemization has been measured at low concentrations in a refrigeratorin aqueous buffer solutions at pH 8, 9.3, 10 and 11.2. Thestereochemical stability was measured by comparing the optical purityfor the (−)-isomer of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazolein buffer solution immediately after dissolving and after several days.The measurement was performed by chromatography on an analytical chiralcolumn. The surprising high stereochemical stability in alkalineconditions for the compounds of invention is exemplified by the factthat no racemization for the test compound was obtained at pH 11.2 evenafter 21 days. At pH 8, 9.3 and 10, the chemical degradation of thecompound is more apparent which makes the racemization measurement moredifficult to perform, however at none of these pH values a detectableracemization was obtained after 16 days.

In another racemization experiment with the optically pure compounds ofthe invention, an aqueous phosphate buffer solution (pH=11) of the(+)-isomer of5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolesodium salt (c=10⁻⁵M) was warmed for 26 hours at 37° C. without anyracemization at all being observed.

1. An optically pure enantiomeric compound comprising a Na⁺, Mg²⁺, Li⁺,K⁺, Ca²⁺ or N⁺(R)₄ salt of(+)-5-methoxy-2-[[(4-methoxy-3,5,dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleor(−)-5-methoxy-2-[[(4-methoxy-3,5,dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole,wherein R is an alkyl with 1-4 carbon atoms. 2-34. (canceled)